Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) remains one of the most important and challenging global infectious disease problems, despite the widespread use of the M. bovis bacillus Calmette-Guerin (BCG) vaccine and the availability of effective drug therapies. Although BCG vaccination remains in widespread in much of the world, its use has had at most a marginal effect on reducing the global burden of disease. Substantial efforts and resources continue to be directed at improving BCG, or developing new vaccines based on other live attenuated organisms or prime-boost protocols. However, none of these efforts have yet yielded a vaccine that represents a clear improvement over BCG. Major knowledge gaps continue to present barriers to effective TB vaccine design, including the lack of certainty on the specific target antigens against which protective T cell responses should be directed. Most previous and current efforts to develop improved vaccines for TB have focused on the use of immunodominant secreted protein antigens produced by the bacterium. These antigens are the most prominent targets of adaptive immune responses in animals and humans with active or latent tuberculosis, and have been frequently proposed as prime components for incorporation into new vaccines. However, many attempts to improve vaccination by incorporating immunization against various immunodominant antigens have not resulted yet in clear improvements over the standard BCG vaccine. The current proposal is for an exploratory project to establish better targets for CD4+ T cell responses that can deliver bactericidal immunity and resistance to progression of Mtb infection. In this proposal, we will pursue the hypothesis that the true ?Achilles heel? of Mtb is more likely to be found among the many subdominant or cryptic antigens of the bacterium. Using a novel approach to immunization in mice, we have discovered that the structural proteins of the Mtb ribosome constitute a family of cryptic antigens in Mtb that may have the potential to induce CD4+ T cell responses that mediate unprecedented levels of bactericidal and protective immunity. The studies outlined for this two year proposal will develop this discovery further as a novel approach to the creation of more effective TB vaccines.